EP0211745B1 - Dérivé d'acide acétohydroxamique, procédé de préparation et utilisation en thérapeutique - Google Patents

Dérivé d'acide acétohydroxamique, procédé de préparation et utilisation en thérapeutique Download PDF

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Publication number
EP0211745B1
EP0211745B1 EP86401643A EP86401643A EP0211745B1 EP 0211745 B1 EP0211745 B1 EP 0211745B1 EP 86401643 A EP86401643 A EP 86401643A EP 86401643 A EP86401643 A EP 86401643A EP 0211745 B1 EP0211745 B1 EP 0211745B1
Authority
EP
European Patent Office
Prior art keywords
crl
nitro
chloro
dose
acetohydroxamic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP86401643A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0211745A2 (fr
EP0211745A3 (en
Inventor
Louis Lafon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cephalon France SAS
Original Assignee
Laboratoire L Lafon SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoire L Lafon SA filed Critical Laboratoire L Lafon SA
Priority to AT86401643T priority Critical patent/ATE47837T1/de
Publication of EP0211745A2 publication Critical patent/EP0211745A2/fr
Publication of EP0211745A3 publication Critical patent/EP0211745A3/fr
Application granted granted Critical
Publication of EP0211745B1 publication Critical patent/EP0211745B1/fr
Expired legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups

Definitions

  • the present invention relates to an acetohydroxamic acid derivative as a new industrial product, namely 2- (5-chloro-4-nitro-2 - methoxybenzamido) -acetoohydroxamic acid. It also relates to its preparation process and its use in therapy, in particular as a sedative agent.
  • the CRL 40 636 according to the invention is remarkable for its sedative effects, while (i) CRL 40 473 has moderate antidepressant and sedative effects, and that (ii) CRL 40 816 is more antidepressant than sedative.
  • a therapeutic composition which is characterized in that it contains, in combination with a physiologically acceptable excipient, 2- (5-chloro-4-nitro-2 - methoxybenzamido) -acetoohydroxamic acid which has for structural formula:
  • the compound according to the invention can be prepared according to a method known per se by application of conventional reaction mechanisms.
  • the process which is recommended here consists in reacting the hydroxylamine with a lower alkyl 5-chloro-4-nitro-2-methoxybenzamido-acetamide in C t -C s , at room temperature (15-20 ° C), for at least 1 h, preferably for at least 4 h, at a rate of 1 to 1.1 moles of NH 2 0H for one mole of alkyl 5-chloro-4-nitro - 2-methoxybenzamidoacetate.
  • a solution of hydroxylamine is prepared with 5.6 g (0.08 mole) of hydroxylamine hydrochloride and 3.68 g (0.16 Atg) of sodium in 250 ml of methanol. 23.8 g (0.075 mol) of ethyl 5-chloro-4-nitro-2-methoxybenzamidoacetate are added, and the mixture is left in contact overnight. The sodium salt is drained, washed with methanol and dried. The dried product thus obtained is taken up in 200 ml of water, filtered and the filtrate is precipitated with 3N HCl. It is wrung, washed with water, dried. By recrystallization of the weight mixture C 2 H 5 OH-H 2 O (96: 4), CRL 40 636 is obtained with a yield of 44%. Mp 196-198 ° C (with decomposition).
  • CRL 40 636 is not toxic.
  • the DL-0 (maximum non-lethal dose) in mice intraperitoneally is greater than 1024 mg / kg.
  • Apomorphine is injected subcutaneously at a dose of 0.5 mg / kg in groups of 6 rats 0.5 h after the administration of CRL 40 636. It is observed that the stereotypies induced by apomorphine in rats are not modified by CRL 40 636.
  • CRL 40 636 strongly antagonizes the amphetamine stereotypies (whereas the CRL 40 816 mentioned above only causes a moderate reduction in said stereotypies only from the dose of 256 mg / kg ip); we also observe that, if the antagonism of these stereotypes by CRL 40 636 is very intense at the start, it seems to disappear quickly.
  • CRL 40 636 does not modify hypothermia or reserpinic ptosis.
  • Oxotremorine (0.5 mg / kg) is injected intraperitoneally into batches of 6 mice half an hour after administration of CRL 40 636. It is observed that CRL 40 636 which exerts a significant hypothermic effect at doses 32, 128 and 512 mg / kg, does not oppose these doses to the hypothermia induced by oxotremorine, that it has no effect vis-à-vis the tremors caused by oxotremorine , but that it seems to lead to a prolongation of the lacrimation (which implies an action on the peripheral cholinergic symptoms).
  • CRL 40 636 does not cause an increase in the number of punished passages; that, at high doses, it causes motor incapacity in 30% of animals; and that it does not modify the convulsive and lethal effects of electroshock.
  • mice Half an hour after receiving CRL 40 636, the mice (6 per dose, 12 controls) are placed on an actimeter where their motility is recorded for 0.5 h. It is noted that, at the doses of 128 and 512 mg / kg, CRL 40 636 causes a significant reduction in spontaneous motility, while the aforementioned CRL 40 816 causes only a moderate reduction in said motility at the dose of 512 mg / kg.
  • mice groups of 3 male mice (each mouse weighing approximately 20 g) receive the products to be tested, namely CRL 40 636 (example 1), CRL 40 473 (CP-1) and CRL 40 816 (CP-2), intraperitoneally in an aqueous solution of gum arabic, at a rate of three cages per product and per dose and six cages for control animals receiving only the aqueous solution of gum arabic intraperitoneally.
  • CRL 40 636 example 1
  • CRL 40 473 CP-1
  • CRL 40 816 CP-2
  • mice After 18 hours of stay in the actimeters, the mice (6 per dose, 12 controls) receive CRL 40 636. They are immediately replaced in their respective enclosures and, half an hour later, their motility is recorded for 30 minutes.
  • CRL 40 636 does not cause a clear resumption of motor activity in the mouse accustomed to its enclosure.
  • mice Half an hour after receiving CRL 40 636, the mice (10 per dose, 20 controls) are subjected to acute hypobaric anoxia [depression of 600 mmHg (ie approximately 8 ⁇ 10 4 Pa) in 90 seconds; 45 seconds relaxation], then they are placed in an actimeter where their motility is recorded for 10 minutes.
  • acute hypobaric anoxia depression of 600 mmHg (ie approximately 8 ⁇ 10 4 Pa) in 90 seconds; 45 seconds relaxation
  • CRL 40 636 does not cause a marked improvement in motor recovery in mice whose motility has been depressed following a brief stay in an enclosure at reduced pressure.
  • CRL 40 636 does not modify the time of onset of convulsions and death following an asphyxial anoxia caused by a curarizing agent.
  • a complementary test was carried out with the product according to the invention, the latter being administered in suspension in an aqueous solution of gum arabic, by gastric route, in a volume of 5 ml / kg, to batches of 6 male rats 0 , 5 h or 1 h before the administration of 2 mg / kg intraperitoneal amphetamine.
  • CRL 40 636 briefly antagonizes the stereotypies induced by amphetamine in rats.
  • CRL 40 636 presents in its neuropsychopharmacological profile essentially very intense sedative effects, objectified by hypomotility, hypothermia, a decrease in reactivity, and a decrease in intergroup aggressiveness, and that it is practically devoid of antidepressant effects (no antagonism of hypothermia induced by apomorphine, reserpine and oxotremorine).
  • Clinically CRL 40 636 has been shown in adult men to be an excellent oral sedative at a daily dose of 50 to 100 mg.
  • the dosage to be used consists in particular of administering two to four included or capsules per day each containing 25 mg of CRL 40 636. It is recommended the use of 2- (5-chloro - 4-nitro-2-methoxybenzamido) acid -acetohydroxamic for obtaining a sedative medicament intended for use in therapy in patients needing such a medicament, in particular in the cases of overexcitation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Anesthesiology (AREA)
  • Pain & Pain Management (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)
EP86401643A 1985-07-31 1986-07-23 Dérivé d'acide acétohydroxamique, procédé de préparation et utilisation en thérapeutique Expired EP0211745B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT86401643T ATE47837T1 (de) 1985-07-31 1986-07-23 Acetohydroxamsaeurederivat, herstellungsverfahren und therapeutische verwendung.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8511685A FR2585699B1 (fr) 1985-07-31 1985-07-31 Derive d'acide acetohydroxamique, procede de preparation et utilisation en therapeutique
FR8511685 1985-07-31

Publications (3)

Publication Number Publication Date
EP0211745A2 EP0211745A2 (fr) 1987-02-25
EP0211745A3 EP0211745A3 (en) 1987-12-02
EP0211745B1 true EP0211745B1 (fr) 1989-11-08

Family

ID=9321806

Family Applications (1)

Application Number Title Priority Date Filing Date
EP86401643A Expired EP0211745B1 (fr) 1985-07-31 1986-07-23 Dérivé d'acide acétohydroxamique, procédé de préparation et utilisation en thérapeutique

Country Status (13)

Country Link
US (1) US4713395A (da)
EP (1) EP0211745B1 (da)
JP (1) JPS6229563A (da)
AT (1) ATE47837T1 (da)
AU (1) AU583219B2 (da)
CA (1) CA1250001A (da)
DE (1) DE3666808D1 (da)
DK (1) DK361586A (da)
ES (1) ES2004338A6 (da)
FR (1) FR2585699B1 (da)
GR (1) GR862008B (da)
PT (1) PT83110B (da)
ZA (1) ZA865684B (da)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3787569A (en) * 1971-05-17 1974-01-22 Morton Norwich Products Inc 2-p-nitro-or p-chlorobenzamido-acetohydroxamic acid
US4083996A (en) * 1976-02-20 1978-04-11 Eisai Co., Ltd. Novel hydroxamic acid derivatives and medicaments for treatment of urolithiasis and pyelonephrosis comprising such derivatives
GB1574822A (en) * 1976-03-23 1980-09-10 Lafon Labor Acetohydroxamic acid derivatives and pharmaceutical compositions thereof

Also Published As

Publication number Publication date
ATE47837T1 (de) 1989-11-15
FR2585699B1 (fr) 1988-03-11
DK361586A (da) 1987-02-01
PT83110A (fr) 1986-08-01
FR2585699A1 (fr) 1987-02-06
GR862008B (en) 1986-12-23
JPS6229563A (ja) 1987-02-07
DK361586D0 (da) 1986-07-30
EP0211745A2 (fr) 1987-02-25
ZA865684B (en) 1987-04-29
AU583219B2 (en) 1989-04-20
DE3666808D1 (en) 1989-12-14
AU6071286A (en) 1987-02-05
US4713395A (en) 1987-12-15
CA1250001A (fr) 1989-02-14
ES2004338A6 (es) 1989-01-01
EP0211745A3 (en) 1987-12-02
PT83110B (pt) 1989-02-28

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